Beta-adrenoceptor Blocking Research Articles

The Effects of Nebivolol-Gefitinib-Loratadine Against Lung Cancer Cell Lines.

Non-small-cell lung cancer (NSCLC) is the most frequently diagnosed malignancy and the first cause of cancer-related death. Thus, finding alternative therapeutic options is crucial. Drug repurposing offers therapeutic options in a simplified and affordable manner, especially to cancer patients in developing countries. Several drugs including antihistamines and beta-adrenergic receptor blockers (beta-blockers) display antiproliferative properties on cancer cells. Interestingly, NSCLC patients who had used either antihistamines or beta-blockers showed improved response to chemotherapy or reduced mortality in comparison to non-users of any of these drugs. However, combination therapy is gaining substantial interest in many cancers including non-EGFR mutated NSCLC. Here, we investigated the antineoplastic effect of the combination of the antihistamine loratadine, the beta-blocker nebivolol, and the tyrosine-kinase inhibitor gefitinib on NSCLC cell lines. A-549 and NCI-H1975 cell lines were used. The effect of nebivolol, gefitinib, and loratadine on the metabolic activity was studied using the MTT assay. The inhibitory concentrations (IC20 and IC50) were calculated and used in the drug-combination experiments. Apoptosis was investigated using flow cytometry; and cell survival using the colony formation assay. The combination nebivolol-loratadine-gefitinib produced a significant synergistic effect on inhibiting the metabolic activity and colony formation, as well as on promoting apoptosis in both cell lines. Noteworthy, the effect on the cell line carrying the EGFR mutation (NCI-H1975) was very similar to the cell line that does not exhibit such mutation (A-549 cells). The nebivolol-gefitinib-loratadine combination may be a promising alternative for lung cancer treatment.

Association of hypertension and the risk of cancer: a study based on the UK Biobank

Abstract Introduction With the increasing incidence rate of hypertension and carcinoma, there is a growing interest in investigating the potential link between these two diseases. The subdiscipline of hypertension, Onco-hypertension, has been proposed and attracted much attention. However, there are still few researches on this subdiscipline. Purpose This study aims to investigate the relationship between hypertension and the occurrence of cancer. Additionally, we explore whether anti-hypertensive treatment has any impact on the incidence of cancer. Methods This study involved 244,496 participants recruited between 2006-2010 from the UK Biobank, with 21,765 participants were diagnosed with the hypertension according to the ICD10 coding. The Cox regression was used to analyse the the risk of cancer associated with hypertension. The effect of anti-hypertensive treatment on the occur of cancer was also verified according to the Cox regression and the Drug target Mendelian randomization. Results Compared to those participants without hypertension, those people with hypertension have higher risk of the occur of cancer(adjusted hazard ratio(aHR) 1.35, 95% confidence interval(CI)1.3-1.4), especially in breast cancer(aHR 1.43, 95% CI 1.27-1.61), prostate cancer(aHR 1.85, 95% CI 1.7-2.02), lung cancer(aHR 2.15, 95% CI 1.86-2.48), renal cancer(aHR 1.91, 95% CI 1.46-2.49), pancreas cancer(aHR 1.55, 95% CI 1.2-2). Compared to those people with hypertension but without anti-hypertensive treatment, the anti-hypertensive treatment increase the cancer risk(aHR 1.19, 95% CI 1.06-1.33). However, thiazide diuretic have protect effect for hypertension patients on occur of the prostate cancer (aHR 0.74, 95% CI 0.61-0.89) and beta-receptor blocker have protect effect for hypertension patients on occur of the lung cancer (aHR 0.71, 95% CI 0.54-0.93). The result of Drug target Mendelian randomization shows the anti-hypertensive treatment have no significant effect on the risk of cancer. Conclusion The onset of high blood pressure is linked to an elevated risk of several cancers. However, it cannot be conclusively determined whether the use of medications for high blood pressure increases or decreases the overall risk of cancer. This study provides instructive evidences for the further study of Onco-hypertension.The result of main analyseThe analyse of the antihypertensive drug

Topical application of beta-blockers accelerates epithelialization to mesh skin grafted full-thickness burn in sheep

Aim : Beta-adrenergic receptor blockers are conventionally used for the treatment of hypertension, tachycardia, and glaucoma. Research has shown that beta-blockers can accelerate wound epithelialization. In this study, we tested the efficacy of the beta-blocker timolol in an ovine model of grafted full-thickness burn wound healing, which closely mimics clinical scenarios. Methods : Six full-thickness burn wounds were created on the sheep’s posterior surface. Twenty-four hours later, eschars were excised and meshed skin was grafted (Day0). The wounds in the treatment group received topical application of timolol. Blood flow was measured using a blood perfusion imager. Cardiovascular hemodynamics and blood glucose levels were recorded daily. The epithelialization rate on Day 14 was determined by planimetric assay and analyzed by paired t -test. The days that the epithelialization rate exceeded 85%, 90%, and 95% were analyzed by survival analysis. To assess the potential influence of TGFβ, epithelial-mesenchymal transition (EMT), or myofibroblast activation (MFA) on wound healing, the RNA abundance of gene products related to these pathways was measured by reverse transcription and quantitative polymerase chain reaction (RT-qPCR). Results : The epithelialization rate on Day 14 was significantly higher in the treatment group. The days that the epithelialization rate exceeded 85%, 90%, and 95% were significantly shorter in the treatment group. There was no significant difference in wound blood flow or RNA abundance related to TGFβ, EMT, or MFA-related pathways among the groups at any time point. Conclusion : The results demonstrate that the beta-blocker timolol accelerates epithelialization of mesh skin grafted full-thickness burn wounds through a mechanism other than improving wound blood flow.

7246 Cardiac Paraganglioma: A Rare Entity

Abstract Disclosure: L. Javed: None. L. Jonea: None. Cardiac paragangliomas are an exceptionally uncommon subset of neuroendocrine neoplasms. We present a case of a patient presenting with this condition. 70-year-old woman with pertinent past medical history of chronic veinous insufficiency complicated by recurrent abscesses of her right leg since venaseal procedure. The patient had positive IgG lambda on immunofixation that raised concerns for MGUS. Therefore, a F-18 FDG PET-CT scan was performed for further evaluation. PET-CT revealed a hypermetabolic mass in the upper inner right thigh and the right atrium (SUV 17.6) raising concern for septic thrombi. She was admitted in the hospital for initiation of antibiotic therapy. Transesophageal echocardiogram (TEE) revealed a 4.5 cm x 4.0 cm mass in the right atrioventricular (AV) groove region, extending over the root of the main pulmonary artery. Following discharge, despite completing six weeks of IV antibiotic therapy a CT scan on a subsequent clinic visit revealed the same mass as seen on TEE. CT imaging raised suspicion of neuroendocrine tumor. This led to referral to the endocrinology department. Laboratory results showed elevated normetanephrine and dopamine levels increasing likelihood of paraganglioma. Lab Results: 24 hr urine normetaneprhine :7197(N ≤ 376 mcg), 24 hr urinary dopamine :879 (N ≤400 mcg), 24 urinary metanephrine: 84 (N ≤96 mcg) & 24 hr urinary epinephrine <3 (N ≤20 mcg). Her home systolic blood pressure readings varied between 120’s & 170’s. She was initiated on Prazosin 1 mg daily in addition to the existing antihypertensive medications of nebivilol, amlodipine & furosemide. Few months later, this patient successfully underwent cardiac mass resection. Histologic findings of the resected mass were consistent with paraganglioma. Post-surgery, anti-hypertensive medications were discontinued, and blood pressure normalized to systolic readings in the 90s to 120s and diastolic readings in the 60s to 80s. Repeat biochemical tests indicated a normalization of normetanephrine & dopamine levels, validating the success of the resection. This case features an extremely rare entity cardiac paraganglioma that had an atypical clinical manifestation of being asymptomatic. Timely diagnosis and appropriate management are crucial for patient outcomes. Surgical intervention, although fundamental, bears significant risks, necessitating meticulous preoperative management to mitigate potential complications. The medical approach focuses on averting perioperative complications such as hypertensive crisis, cardiac arrhythmias and myocardial infarction. This is achieved by administering alpha and beta adrenoceptor blockers for a minimum of two weeks before the scheduled surgery. Regular follow up is also essential due to the unpredictable malignant potential of these tumors. Presentation: 6/3/2024

Studies on Propranolol hydrochloride floating tablets formulated with different concentrations of Aegle marmelos gum

This research employs Aegle marmelos gum in various ratios as a natural polymer to formulate and assess Propranolol hydrochloride floating tablets. Because of its high solubility and permeability, propranolol hydrochloride, a non-selective beta-adrenergic receptor blocker, has a restricted bioavailability. Floating tablets are intended to improve the absorption and bioavailability of drugs by staying afloat in the stomach. Aegle marmelos gum (AMG) was used as a polymer in varied ratios to create distinct formulations. The tablets were then tested for a number of characteristics, including hardness, friability, drug content, in vitro buoyancy, and drug release profiles. The findings showed that the Aegle marmelos gum content had a major impact on the tablets' floating qualities and drug release characteristics.

High-sensitivity cardiac troponin I-guided combination angiotensin receptor blockade and beta blocker therapy to prevent anthracycline cardiotoxicity: the Cardiac CARE RCT

Background Anthracycline-induced cardiotoxicity has a variable incidence, and the development of left ventricular dysfunction is preceded by rises in plasma cardiac troponin concentrations. Beta-adrenergic receptor blocker and renin-angiotensin-system inhibitor therapies have been associated with modest cardioprotective effects in unselected patients receiving anthracycline chemotherapy. Methods In a multicentre prospective randomised open-label blinded end-point trial, patients with breast cancer and non-Hodgkin lymphoma receiving anthracycline chemotherapy underwent plasma high-sensitivity cardiac troponin concentration monitoring and cardiac magnetic resonance imaging before and 6 months after anthracycline treatment. Randomised controlled trial – patients at high risk of cardiotoxicity (plasma cardiac troponin I concentrations in the upper tertile during chemotherapy) were randomised to standard care plus cardioprotection (combination carvedilol and candesartan therapy) or standard care alone. The primary end point was 6-month change in left ventricular ejection fraction. Prognostic cohort study – in low-risk non-randomised patients with plasma cardiac troponin I concentrations in the lower two tertiles, we hypothesised the absence of a 6-month change in left ventricular ejection fraction (± 2%). Results Between October 2017 and June 2021, 175 patients (mean age 53 years; 87% female; 71% breast cancer) were recruited. Patients randomised to cardioprotection (n = 29) or standard care (n = 28) had mean left ventricular ejection fractions of 65.7 ± 6.6% and 64.9 ± 5.9%, respectively, at 6 months. Twenty patients (68.9%) were adherent to cardioprotection therapy at 6 months. Adverse events were more commonly reported in the cardioprotection group, with 71.4% of patients having at least one adverse event compared with 12.7% non-randomised and 10.3% standard care patients. After adjusting for age, pre-treatment left ventricular ejection fraction and planned anthracycline dose, the estimated mean percentage-point difference in 6-month left ventricular ejection fraction between the cardioprotection and standard care groups was –0.4% (95% confidence interval –3.59 to 2.85%; p = 0.82). In low-risk non-randomised patients, baseline and 6-month left ventricular ejection fractions were 69.3 ± 5.7% and 66.4 ± 6.3%, respectively (estimated mean difference 2.9%, 95% confidence interval 1.45 to 4.28%; p = 0.92, not equivalent). The main secondary objective of demonstrating zero percentage-point change with equivalence of ± 2% was not met. Conclusions Combination candesartan and carvedilol therapy had no demonstrable cardioprotective effect in patients receiving anthracycline-based chemotherapy with high-risk on-treatment plasma cardiac troponin I concentrations. Low-risk non-randomised patients had similar modest declines in left ventricular ejection fraction, suggesting that the clinical utility of routine cardiac troponin monitoring remains undefined. The modest short-term declines in left ventricular ejection fraction suggest that early cardioprotection therapy has a limited role in patients receiving anthracycline-based chemotherapy. Limitations Treatment effect might have been influenced by several patients stopping cardioprotection treatment within 2 months of randomisation. Across all groups, reduction in left ventricular ejection fraction was lower than expected and patients with high-risk cardiac troponin I concentrations did not exhibit a greater fall in left ventricular ejection fraction than low-risk patients. These factors, together with the trial being powered to detect a 5-percentage-point change in left ventricular ejection fraction, mean that a small treatment effect was not excluded. Future work Future work should aim to understand the transition from small changes in cardiac function, 6 months after completion of anthracycline chemotherapy, to the late development of heart failure in this population. Trial registration This trial is registered as ISRCTN24439460 and EudraCT 2017-000896-99. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 15/48/20) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 12. See the NIHR Funding and Awards website for further award information.

Steroidomics-Based Screening for Primary Aldosteronism: Impact of antihypertensive Drugs.

Diagnosis of primary aldosteronism (PA) is complicated by the need to withdraw antihypertensive medications that interfere with test results, particularly renin. This study examined whether machine learning-based steroid-probability scores offer a renin measurement-independent approach for testing less prone to interference than the aldosterone-to-renin ratio (ARR). This prospective multicenter cohort study involved the use of plasma steroidomics and the ARR in 839 patients tested for PA, including 190 with and 578 without PA (71 indeterminate). Receiver operating characteristic curves for steroid-probability scores and the ARR were examined with and without interfering medications. Impacts of individual medications on plasma aldosterone, 18-oxocortisol, 18-hydroxycortisol, steroid-probability scores, renin, and ARRs were examined by multivariable and paired analyses in patients with and without PA. Receiver operating characteristic curves indicated a significant impact of interfering antihypertensive medications on the diagnostic performance of the ARR and minimal impact on steroid-probability scores. Mineralocorticoid receptor antagonists increased plasma aldosterone, 18-oxocortisol, and 18-hydroxycortisol in patients without PA and resulted in false-positive test results for steroid-probability scores and false-negative results for the ARR. Diuretics increased aldosterone, 18-oxocortisol, and steroid-probability scores in patients without PA, whereas angiotensin-converting enzyme inhibitors decreased aldosterone, steroid-probability scores, and ARRs. Beta-adrenoceptor blockers, dihydropyridine calcium channel blockers, and angiotensin receptor blockers had negligible impact on mineralocorticoids and steroid-probability scores. Among antihypertensive drugs that impact plasma aldosterone, 18-oxocortisol, and 18-hydroxycortisol, mineralocorticoid receptor antagonists stood out as a cause of false-positive results for derived steroid-probability scores. Other antihypertensives have minimal or no impact, an advantage for use of steroid-probability scores over the ARR when those medications cannot be withdrawn. URL: https://drks.de/search/en/trial/DRKS00017084; Unique identifier: DRKS00017084.

Antihypertensive Drugs for the Prevention of Atrial Fibrillation: A Drug Target Mendelian Randomization Study.

We investigated the potential impact of antihypertensive drugs for atrial fibrillation (AF) prevention through a drug target Mendelian randomization study to avoid the potential limitations of clinical studies. Validated published single-nucleotide polymorphisms (SNPs) that mimic the action of 12 antihypertensive drug classes, including alpha-adrenoceptor blockers, adrenergic neuron blockers, angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers, beta-adrenoceptor blockers, centrally acting antihypertensive drugs, calcium channel blockers, loop diuretics, potassium-sparing diuretics and mineralocorticoid receptor antagonists, renin inhibitors, thiazides and related diuretic agents, and vasodilators were used. We estimated, via their corresponding gene and protein targets, the downstream effect of these drug classes to prevent AF via systolic blood pressure using 2-sample Mendelian randomization analyses. The SNPs were extracted from 2 European genome-wide association studies for the drug classes (n=317 754; n=757 601) and 1 European genome-wide association study for AF (n=1 030 836). Drug target Mendelian randomization analyses supported the significant preventive causal effects of lowering systolic blood pressure per 10 mm Hg via alpha-adrenoceptor blockers (n=11 SNPs; odds ratio [OR], 0.34 [95% CI, 0.21-0.56]; P=2.74×10-05), beta-adrenoceptor blockers (n=17 SNPs; OR, 0.52 [95% CI, 0.35-0.78]; P=1.62×10-03), calcium channel blockers (n=49 SNPs; OR, 0.50 [95% CI, 0.36-0.70]; P=4.51×10-05), vasodilators (n=19 SNPs; OR, 0.53 [95% CI, 0.34-0.84]; P=7.03×10-03), and all 12 antihypertensive drug classes combined (n=158 SNPs; OR, 0.64 [95% CI, 0.54-0.77]; P=8.50×10-07) on AF risk. Our results indicated that lowering systolic blood pressure via protein targets of various antihypertensive drugs seems promising for AF prevention. Our findings inform future clinical trials and have implications for repurposing antihypertensive drugs for AF prevention.

Abstract LB135: Effects of acute psychological stress on DNA damage levels in peripheral blood mononuclear cells: An experimental study with healthy human volunteers

Abstract Increased levels of DNA damage in human peripheral blood mononuclear cells (PBMC), as indicated by classic alkaline comet and γ-H2AX assays, have been widely used in toxicology and epidemiology studies of potential environmental carcinogens. To date, however, little research has explored the possibility that exposure to acute psychological stresses in daily life may acutely increase levels of DNA damage and thus, much like repeated tobacco use, may cumulatively contribute to lifetime cancer risk. The purpose of the present experimental study was to provide a first critical test of the hypothesis that exposure of healthy humans to a brief psychological stress results in increased levels of DNA damage. We also tested preventative effects of a beta-adrenergic receptor blocker (propranolol), a mechanistic pathway for psychological stress effects on DNA supported by preclinical research. Healthy volunteers were recruited by multiple strategies including targeted outreach (telephone/email), with oversampling for age, sex, and minority status. Eligibility was confirmed by self-report, clinical testing (blood & urine), and MD review. On the experimental day, participants were randomized to receive either a single dose of propranolol (80mg) or a placebo. After a 60 min rest period with video distraction, all participants (n=123; 48.8% ≥ 40yr; 52% women; 52% minority) underwent a well-established, 15-minute stress challenge, a speech task and mental arithmetic (Trier Social Stress Test, TSST), with psychological stress confirmed by visual analog scales. Blood samples were collected (via IV line) immediately before and after the TSST. As the primary study outcome, DNA damage in PBMC was assessed (blind) with Comet IV software (% tail intensity) following single cell gel electrophoresis under alkaline conditions with and without in vitro exposure to 25uM H2O2 (comet assay). For a subset of participants with sufficient frozen PBMC samples available (n=43), levels of pan-nuclear γ-H2AX were determined with a validated, sensitive, immunoblot method that detects H2AX phosphorylation at Ser139, and expresses γ-H2AX as the ratio of p-Ser139-H2AX to total H2AX. Exploratory nonparametric analyses revealed that undergoing the TSST significantly increased levels of DNA damage in PBMC (H2O2 comet assay [p<.001] and γ-H2AX biomarker [p=.03], Wilcoxon tests) in the group of participants that was randomized to pretreatment with placebo. In the group pretreated with propranolol before the TSST, a significant increase in γ-H2AX was not found. Conclusion. Supporting the study hypothesis that acute stress can increase levels of DNA damage, the results of the present study highlight the potential importance of additional research to address the possibility that repeated exposures to acute life stresses may cumulatively contribute to increased lifetime risk of cancer. Citation Format: Dana H. Bovbjerg, John Schmitz, Kurt D. Ackerman, Scott R. Beach, Albert D. Donnenberg, Jessica Manculich, Matthew F. Muldoon, Patricia L. Opresko, Patrick M. Tarwater, Hong Wang, Frank J. Jenkins. Effects of acute psychological stress on DNA damage levels in peripheral blood mononuclear cells: An experimental study with healthy human volunteers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB135.

Abstract 3391: Effects of repeated psychological stress on NNK-induced lung cancer development in young female mice

Abstract Lung cancer is the second most common cancer in both men and women in the US and the leading cause of cancer death. Among younger US women, lung cancer incidence rates have in recent years become higher than rates seen in men, despite comparable histories of tobacco use. The possible contribution of stress to higher lung cancer risk in young women has received little research attention despite preclinical evidence that exposure to stress-related neuroendocrine responses can cause DNA damage. The present study used a well-established lung cancer model in young female mice (in vivo exposure to NNK) along with a mouse stress model to explore their independent and combined effects on lung cancer development. In addition, we explored one possible biological pathway by chronic administration of a beta-adrenergic receptor blocker (propranolol). We also tested the use of in vivo imaging for repeated monitoring of tumor development over time. Cohort 1 (n=60) had 4 groups: Home cage control, NNK treatment alone, repeated stress (RS) alone and NNK+RS. Cohort 2 (n=60) had the same 4 groups with the addition of administration of propranolol in drinking water. Cohort 3 (n=48, imaging cohort) had 3 groups: Home cage control, NNK alone and NNK+RS. FVB/N (4-6 wk) were purchased from a commercial supplier and acclimated with gentle handling for two weeks. The repeated stress protocol began week-3 and continued for the duration of the study. It combined two well-established rodent models: social disruption stress via changes in cage mates at the time of cage cleaning (2x/week) and a 90-minute restraint stress immediately prior to cage change (1x/week). NNK or saline treatment began on week-4 (IP; 2x/week; 3 mg/injection) and continued for 4 weeks. 21 weeks after stress initiation, the mice in cohorts 1 and 2 were sacrificed, lungs removed, inflated and tumors counted and sized. Mice in cohort 3 were imaged by Hounsfield-calibrated micro-CT (μCT) at baseline, 14, 19 and 23 weeks. The entire lung space, excluding the heart, was defined as a volumetric region of interests (VOIs). The VOIs were subjected to thresholding to segment the lungs into air space and tissue space compartments. The volume of tissue space of each animal was ratioed against its own baseline tissue space volume. Results from Cohort 1 revealed significantly greater numbers and overall size of lung tumors in stressed mice that received NNK. No significant effects were seen in the absence of NNK. Results from Cohort 2 revealed no significant differences between stressed and unstressed groups treated with propranolol. Cohort 3 revealed a pattern of results with stressed mice generally showing the highest lung tumor volume levels (Hounsfield Units), which reached significance at 19 weeks in preliminary analyses. Conclusion: In this study, we found that repeated stress increased lung tumor burden in female mice treated with NNK, and that a beta-adrenergic pathway may be involved. Citation Format: Frank Jenkins, Laura P. Stabile, Jessie R. Nedrow, Kathryn Day, Joseph D. Latoche, Patrick M. Tarwater, Jessica Manculich, Dana H. Bovbjerg. Effects of repeated psychological stress on NNK-induced lung cancer development in young female mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3391.

Long-term intraocular pressure-lowering efficacy and safety of ripasudil-brimonidine fixed-dose combination for glaucoma and ocular hypertension: a multicentre, open-label, phase 3 study.

To evaluate the long-term efficacy and safety of ripasudil-brimonidine fixed-dose combination (RBFC), a new intraocular pressure (IOP)-lowering medication for glaucoma and ocular hypertension (OHT). This prospective, multicentre (23 sites in Japan), open-label study enrolled patients with primary open-angle glaucoma (POAG), OHT or exfoliative glaucoma and assigned them to one of four combination therapy cohorts, based on previous treatment(s) received: prostaglandin (PG) analogue (Cohort 1); PG analogue and beta-adrenoceptor blocker (β-blocker) (Cohort 2); PG analogue, β-blocker and carbonic anhydrase inhibitor (Cohort 3); or other/no treatment (Cohort 4). After a ≥ 4-week screening period, eligible patients received twice-daily RBFC for 52weeks in addition to the treatments they were already receiving. Efficacy was assessed by change in IOP from baseline through week 52. Adverse events and adverse drug reactions (ADRs) were monitored throughout. In total, 179 patients from Cohort 1 (n = 48), Cohort 2 (n = 44), Cohort 3 (n = 41) and Cohort 4 (n = 46) entered the RBFC treatment period. For all cohorts, mean IOP was significantly reduced at 11:00 (2h after instillation of RBFC) through week 52 with the changes from baseline at week 52 of - 2.7 to - 4.1mmHg across cohorts; all p < 0.001. Common ADRs were conjunctival hyperaemia (58%), allergic conjunctivitis (18%) and blepharitis (17%), most of which were mild in severity. These data demonstrated the long-term efficacy and safety of RBFC, both alone and in combination with other anti-glaucoma agents. RBFC may offer a new treatment option for the long-term management of glaucoma and OHT. Japan Registry of Clinical Trials Identifier: jRCT2080225063. 17 February 2020.

Norepinephrine induces anoikis resistance in high-grade serous ovarian cancer precursor cells.

High-grade serous carcinoma (HGSC) is the most lethal gynecological malignancy in the United States. Late diagnosis and the emergence of chemoresistance have prompted studies into how the tumor microenvironment, and more recently tumor innervation, may be leveraged for HGSC prevention and interception. In addition to stess-induced sources, concentrations of the sympathetic neurotransmitter norepinephrine (NE) in the ovary increase during ovulation and after menopause. Importantly, NE exacerbates advanced HGSC progression. However, little is known about the role of NE in early disease pathogenesis. Here, we investigated the role of NE in instigating anchorage independence and micrometastasis of preneoplastic lesions from the fallopian tube epithelium (FTE) to the ovary, an essential step in HGSC onset. We found that in the presence of NE, FTE cell lines were able to survive in ultra-low-attachment (ULA) culture in a β-adrenergic receptor-dependent (β-AR-dependent) manner. Importantly, spheroid formation and cell viability conferred by treatment with physiological sources of NE were abrogated using the β-AR blocker propranolol. We have also identified that NE-mediated anoikis resistance may be attributable to downregulation of colony-stimulating factor 2. These findings provide mechanistic insight and identify targets that may be regulated by ovary-derived NE in early HGSC.

Repurposing antihypertensive drugs for pain disorders: a drug-target mendelian randomization study.

Addressing the rising prevalence of pain disorders and limitations of current analgesics, our study explores repurposing antihypertensive drugs for pain management, inspired by the link between hypertension and pain. We leverage a drug-target Mendelian Randomization (MR) approach to explore their dual benefits and establish causal connections. A comprehensive compilation of antihypertensive drug classes was undertaken through British National Formulary, with their target genes identified using the DrugBank database. Relevant single nucleotide polymorphisms (SNPs) associated with these targets were selected from published genomic studies on systolic blood pressure (SBP) as genetic instruments. These SNPs were validated through MR against acute coronary artery disease (CAD) to ensure genes not linked to CAD were excluded from acting as proxies for antihypertensive drugs. An MR analysis of 29 pain-related outcomes was conducted using the FinnGen R10 database employing the selected and validated genetic instruments. We utilized the Inverse Variance Weighted (IVW) method for primary analysis, applying Bonferroni correction to control type I error. IVW's multiplicative random effects (MRE) addressed heterogeneity, and MR-PRESSO managed pleiotropy, ensuring accurate causal inference. Our analysis differentiates strong and suggestive evidence in linking antihypertensive drugs to pain disorder risks. Strong evidence was found for adrenergic neuron blockers increasing migraine without aura risk, loop diuretics reducing panniculitis, and vasodilator antihypertensives lowering limb pain risk. Suggestive evidence suggests alpha-adrenoceptor blockers might increase migraine risk, while beta-adrenoceptor blockers could lower radiculopathy risk. Adrenergic neuron blockers also show a potential protective effect against coxarthrosis (hip osteoarthritis) and increased femgenpain risk (pain and other conditions related to female genital organs and menstrual cycle). Additionally, suggestive links were found between vasodilator antihypertensives and reduced radiculopathy risk, and both alpha-adrenoceptor blockers and renin inhibitors possibly decreasing dorsalgianas risk (unspecified dorsalgia). These findings highlight the intricate effects of antihypertensive drugs on pain disorders, underlining the need for further research. The findings indicate that antihypertensive medications may exert varied effects on pain management, suggesting a repurposing potential for treating specific pain disorders. The results advocate for further research to confirm these associations and to explore underlying mechanisms, to optimize pain management practices.

Association between antihypertensive drugs and oral cancer: a drug target Mendelian randomization study

Background: Recent reports have suggested that antihypertensive drugs may play an oncogenic role in common cancers, but it is still uncertain whether this could influence the risk of oral cancer. Through two-sample Mendelian randomization (MR), we sought to assess the causal effect of antihypertensive drugs on oral cancer outcomes.Methods: To proxy the exposure of antihypertensive drugs, we utilized two genetic instruments, including expression quantitative trait loci of drug target genes and genetic variants within or around drug target genes related to blood pressure from genome-wide association studies. Inverse-variance-weighted MR (IVW-MR) and summary-data-based MR (SMR) were employed to compute the instrument effect estimates.Results: It was observed through IVW-MR analysis that there is a positive relationship between KCNH2 (target of beta-adrenoceptor blockers)–mediated blood pressure and oral cancer (odds ratio [OR] = 1.197, 95% confidence interval [CI] = 1.028–1.394). Similarly, SMR analysis demonstrated that a higher expression of KCNH2 (target of beta-adrenoceptor blockers) was linked to a greater risk of oral cancer (OR = 2.223, 95% CI = 1.094–4.516). Both analyses yielded no consistent evidence of other associations.Conclusion: This two-sample MR study proposed a latent causal association between KCNH2 (target of beta-adrenoceptor blockers) inhibition and diminished risk of oral cancer.

Resistive index as predictor of acute kidney injury in patients with non-ST-segment elevation myocardial infarction

BackgroundAcute kidney injury (AKI) is common in patients with non-ST-segment elevation myocardial infarction (NSTEMI). Early detection of AKI is likely to speed diagnosis and implementation of measures to preserve renal function. To evaluate if renal Doppler resistive index (RI) would predict AKI in patients with NSTEMI on presentation in the emergency department. MethodsPatients with NSTEMI at the emergency department were included. The renal Doppler RI was measured. Baseline demographic data and clinical characteristics of patients at admittance were recorded. Based on discharge diagnosis, the patients were divided into AKI group and no-AKI group. Multiple logistic regression analysis was performed to determine predictor variables significantly associated with AKI. ResultsA total of 293 patients were included in the analysis; 44 (15.0 %) developed AKI without need for dialysis. There were statistical differences in the age, incidence of diabetes mellitus and cerebrovascular disease, beta-receptor blockers, serum creatinine and renal index between the two groups. Using multivariate logistic regression analysis, age [OR 1.87; 95 % confidence interval (CI) 1.595–2.585; p = 0.027], diabetes mellitus (OR 2.007, 95 % CI: 1.489–2.793; p = 0.014), serum creatinine (OR 1.817, 95 % CI: 1.568–2.319; p = 0.013), and RI (OR 2.168, 95 % CI: 1.994–4.019; p = 0.003) predicted AKI in patients with NSTEMI. According to receiver operating characteristic (ROC) analysis, RI showed a significantly increased area under the curve (AUC) compared to serum creatitine (AUC: 0.891 vs 0.679; p < 0.001). ConclusionsRenal Doppler RI may be a useful predictor of AKI in patients with NSTEMI in the emergency department.

Nonselective beta-adrenoceptor blocker use and risk of Parkinson’s disease: from multiple real-world evidence

BackgroundPeople with hypertension have a higher risk of developing Parkinson’s disease (PD), epidemiological evidence suggests that multiple antihypertensives may affect the occurrence and development of PD with inconsistent results. With multisource data, we sought to determine whether specific antihypertensive classes elevated or reduced the risk for PD.MethodsWe used a mixed methods approach that combines 4 methodologies. First, we conducted a disproportionality analysis using the reports causing adverse events in the US Food and Drug Administration Adverse Events Reporting System (FAERS) to explore the effect of different classes of antihypertensive medications on the risk of PD; based on the findings from FAERS, a meta-analysis and a UK Biobank cohort analysis were used to further assess the association of drug use with PD; finally, we employed Mendelian randomization (MR) analysis to validate the causal relationship between the drug target and the occurrence of PD.ResultsIn the disproportionality analysis using the FAERS (N = 187,266), nonselective beta-adrenoceptor blockers (NBBs) were demonstrated to have a significant association with PD (reporting odds ratio (ROR) = 3.13; 95% CI 2.33–4.22). In the meta-analysis of 12 studies with 12,183,809 participants, PD risk was elevated in NBBs (RR, 1.64; 95% CI, 1.19–2.09) when stratified by subtypes of BBs. Among the 105,763 participants included in the cohort analysis using data from the UK Biobank, individuals who used NBBs had a significantly increased risk of PD compared to nonusers (HR, 1.47; 95% CI 1.04–2.06). The MR analysis revealed a significant association between higher expression of the β2 adrenergic receptor (ADRB2) gene, a drug target blocked by NBBs, and a reduced risk of PD (OR, 0.85; 95% CI 0.73–0.99).ConclusionsOur comprehensive study indicated that regular NBB use is associated with an increased risk of PD. In light of the detrimental effects of NBBs on PD, some people should choose alternative antihypertensive treatments.

Combination of nicorandil and beta-adrenergic receptor blockers in patients with coronary heart disease: a real-world observational study

Abstract Background and objective Nicorandil and beta-adrenergic receptor blockers (BBs) are commonly used anti-anginal drugs. However, the effect of combined nicorandil and BBs compared with that of BBs alone on long-term clinical outcomes in patients with coronary heart disease (CHD) remains undetermined. Accordingly, a real-world observational study was performed to assess the long-term potential of nicorandil combined with BBs in Chinese patients with CHD. Methods A multicenter retrospective cohort study involving two tertiary healthcare institutions in our city was performed. Adult patients who had been hospitalized for CHD and treated for angina with a combination of nicorandil and BBs or BBs alone between August 2002 and March 2020 were included. The effect of different treatments on the cumulative incidence of major adverse cardiovascular events (MACE) and their components (myocardial infarction [MI], stroke, and all-cause mortality) within a follow-up duration of 2.5 years were analyzed using Kaplan–Meier survival curves. An inverse probability of treatment weighting (IPTW) method was used to adjust for the possible effect of confounding factors. The hazard ratio (HR) and corresponding 95% confidence interval (CI) were calculated using a Cox regression analysis. Sensitivity analyses based on IPTW with trimming or limited to patients admitted after January 1, 2012, were performed to evaluate the robustness of the findings. Results Overall, 4,669 patients receiving the combined treatment and 12,243 receiving BBs alone were included. After IPTW, the results demonstrated that the combined treatment was associated with a significantly reduced incidence of MACE (HR 0.80, 95% CI: 0.73–0.87, P &amp;lt; 0.0001)(Figure 1) and stroke (HR 0.48, 95% CI 0.42–0.54) but not of MI (HR 1.03, 95% CI 0.92–1.15) or all-cause mortality (HR 0.93, 95% CI 0.64–1.37). Interaction analyses were performed for the following subgroups: age (younger than 65 or is and older than 65 years), gender, acute coronary syndrome (ACS), smoking, drinking, revascularization, diabetes and hypertension, and showed a favorable consistency with the primary outcome (Figure 2). Conclusion A combined anti-angina treatment of nicorandil and BBs may be more effective than a treatment of BBs alone in reducing the long-term incidence of MACE in patients with CHD.The Kaplan-Meier curves of the outcomesThe forest plot of the subgroup analysis

Association of Discontinuing Preinjury Beta-Adrenergic Blockade Medications With Mortality in Severe Blunt Traumatic Brian Injury.

Beta-adrenergic receptor blocker (BB) administration has been shown to improve survival after traumatic brain injury (TBI). However, studies to date that observe a benefit did not distinguish between continuation of preinjury BB versus de novo initiation of BB. To determine the effect of continuation of preinjury BB and de novo initiation of BB on risk-adjusted mortality and complications for patients with TBI. Trauma quality collaborative data (2016-2021) were analyzed. Patients were excluded with hospitalization <48 hours, direct admission, or penetrating injury. Severe TBI was identified as a head abbreviated injury scale (AIS) value of 3 to 5. Patients were placed into 4 groups based on the preinjury BB use and administration of BB during hospitalization. Propensity score matching was used to create 1:1 matched cohorts of patients for comparisons. Odd ratios of mortality accounting for hospital clustering were calculated. A sensitivity analysis was performed excluding patients with AIS >2 injuries in all other body regions to create a cohort of isolated TBI patients. A total of 15,153 patients treated at 35 trauma centers were available for analysis. Patients were divided into 4 cohort groupings related to preinjury BB use and postinjury receipt of BB. The odds of mortality was significantly reduced for patients with a TBI on a preinjury BB who had the medication continued in the acute setting (as compared with patients on preinjury BB who did not) (odds ratio [OR], 0.73; 95% confidence interval [CI], 0.54-0.98; P = 0.04). Patients with a TBI who were not on preinjury BB did not benefit from de novo initiation of BB with regard to mortality (OR, 0.83; 95% CI, 0.64-1.08; P = 0.2). In the sensitivity analysis, excluding polytrauma patients, patients on preinjury BB who had BB continued had a reduction in mortality when compared with patients in which BB was stopped following a TBI (OR, 0.65; 95% CI, 0.47-0.91; P = 0.01). Continuing BB is associated with reduced odds of mortality in patients with a TBI on preinjury BB. We were unable to demonstrate benefit from instituting beta blockade in patients who are not on a BB preinjury.

Utilisation and optimisation of beta-adrenergic receptor blockers over a 6-month period among chronic heart failure patients with reduced ejection fraction.

Beta-adrenergic receptor blocker (BARB) drugs are a wide range of medicines that are used in various conditions, including chronic heart failure (HF). Several studies have reported a wide-ranging inappropriate use of evidence-based beta-blockers (EBBBs) in chronic HF in both inpatients and outpatients. To assess the utilisation and optimisation of EBBBs among patients with HF who presented with a reduced ejection fraction (HFrEF). A hospital-based retrospective cross-sectional study was carried out at the Adult University Teaching Hospital (AUTH), in Lusaka, Zambia, where patient medical files for the period of 1 July 2018 to 31 July 2021 were reviewed. Patient information, including file number, age, sex, type of BARB and the dose used, was recorded on the developed and validated checklist. Multivariable regression analysis was performed to identify factors associated with utilisation of BARBs. Of the 173 medical records reviewed, BARBs were utilised in 101 (58.4%) patients. Among the patients who utilised BARBs, 96 (95.0%) were taking EBBBs, while the rest (n=5, 5.0 %) were taking atenolol, which is a non-EBBB. Among the patients who were on EBBBs, none of them received the optimal dose. Age ≥65 years (adjusted odds ratio (aOR) 0.3, 95% confidence interval (CI) 0.17 - 0.64), previous hospitalisation (aOR 0.3, 95% CI 0.13 - 0.51) and furosemide dose ≥40 mg (aOR 0.4, 95% CI 0.21 - 0.64) were significantly associated with lower likelihood of BARB utilisation. New York Heart Association (NYHA) class II (aOR 3.4, 95% CI 1.08 - 10.7), NYHA class III (aOR 4.8, 95% CI 1.65 - 13.7) and patients using at least 5 medications (aOR 5.0, 95% CI 2.91 - 8.77) were independent predictors of BARB utilisation. This study showed that 95.0% of chronic HF patients were utilising EBBBs, and none received the optimal dose as recommended in the guidelines. Pharmacotherapy with EBBBs should be optimised among patients with chronic HfrEF, as these drugs reduce both morbidity and mortality.

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Background. Beta-adrenergic receptor blocker (BARB) drugs are a wide range of medicines that are used in various conditions, including chronic heart failure (HF). Several studies have reported a wide-ranging inappropriate use of evidence-based beta-blockers (EBBBs) in chronic HF in both inpatients and outpatients. Objectives. To assess the utilisation and optimisation of EBBBs among patients with HF who presented with a reduced ejection fraction (HFrEF). Methods. A hospital-based retrospective cross-sectional study was carried out at the Adult University Teaching Hospital (AUTH), in Lusaka, Zambia, where patient medical files for the period of 1 July 2018 to 31 July 2021 were reviewed. Patient information, including file number, age, sex, type of BARB and the dose used, was recorded on the developed and validated checklist. Multivariable regression analysis was performed to identify factors associated with utilisation of BARBs. Results. Of the 173 medical records reviewed, BARBs were utilised in 101 (58.4%) patients. Among the patients who utilised BARBs, 96 (95.0%) were taking EBBBs, while the rest (n=5, 5.0 %) were taking atenolol, which is a non-EBBB. Among the patients who were on EBBBs, none of them received the optimal dose. Age ≥65 years (adjusted odds ratio (aOR) 0.3, 95% confidence interval (CI) 0.17 - 0.64), previous hospitalisation (aOR 0.3, 95% CI 0.13 - 0.51) and furosemide dose ≥40 mg (aOR 0.4, 95% CI 0.21 - 0.64) were significantly associated with lower likelihood of BARB utilisation. New York Heart Association (NYHA) class II (aOR 3.4, 95% CI 1.08 - 10.7), NYHA class III (aOR 4.8, 95% CI 1.65 - 13.7) and patients using at least 5 medications (aOR 5.0, 95% CI 2.91 - 8.77) were independent predictors of BARB utilisation. Conclusion. This study showed that 95.0% of chronic HF patients were utilising EBBBs, and none received the optimal dose as recommended in the guidelines. Pharmacotherapy with EBBBs should be optimised among patients with chronic HfrEF, as these drugs reduce both morbidity and mortality.